Patients with metastatic colorectal cancer (mCRC) and KRAS exon 2 c.38G>A: pGly13Asp (G13D mutation) receiving cetuximab together with irinotecan demonstrated both objective responses and some delay of disease progression, according to phase II study results reported at the European Cancer Congress (ECC 2015), held in Vienna, Austria, 25 - 29 September 2015.
The ICECREAM trial, which was conducted by the Australian Gastrointestinal Trials Group (AGITG), also confirmed the lack of activity of cetuximab monotherapy in patients with G13D mutated mCRC that has previously been reported in smaller series.
Eva Segelov, Department of Medical Oncology, St Vincent’s Clinical School-University of New South Wales, Sydney, Australia, presented the late-breaking ICECREAM results during the Proffered Papers: Gastrointestinal Malignancies - Colorectal Cancer session on 28 September.
Associate Professor Segelov discussed the rationale for the study, explaining that patients with mCRC and KRAS or NRAS mutations are generally not offered treatment with EGFR inhibitors due to lack of response to these agents. There is a 40% incidence of KRAS mutations in CRC, with approximately 19% of these mutations occurring at the KRAS exon 2c.38G>A: pGly13Asp (G13D mutation); the absolute incidence of the G13D mutation is 8% in mCRC.
Patients with KRAS G13D mutation respond to agents targeting EGFR in combination with irinotecan
While patients with KRAS mutations overall tend to show little or no response to agents targeting the epidermal growth factor receptor (EGFR), the G13D mutation has been shown to confer sensitivity to EGFR inhibition in pre-clinical models. Additionally, several retrospective clinical reports suggested treatment benefit with cetuximab in patients with mCRC and G13D mutation that may be similar to that seen in patients with KRAS wild-type tumours. However, these reports have been confounded by small sample sizes and by co-administered chemotherapy, making it difficult to isolate the actual effect of the EGFR inhibitors, according to Dr. Segelov.
Furthermore, adding irinotecan to agents targeting EGFR has been shown to increase the response rate and to delay progression in patients with KRAS unselected mCRC, leading investigators to anticipate that irinotecan could potentiate the response in patients with G13D mutated tumours.
ICECREAM was conducted by the AGITG as a prospective, randomised phase II trial to evaluate the efficacy of cetuximab compared to cetuximab plus irinotecan in patients with mCRC. All patients had ECOG PS 0-2 and were refractory to irinotecan, which was defined as having progressed within 6 months of irinotecan treatment and being intolerant of or refractory to fluoropyrimidine and oxaliplatin.
Patients were stratified by G13D mutation (results presented at ECC) or by wild-type KRAS, NRAS, BRAF and PI3KCA genes (this arm still accruing) and randomised 1:1 to receive either cetuximab at 400 mg/m2 i.v. loading then 250 mg/m2 weekly or the same cetuximab regimen plus irinotecan at 180 mg/m2 every 2 weeks. Patient characteristics were well balanced between treatment groups, except age (61 versus 66 years), time since first metastatic diagnosis (19.1 versus 28.1 months), and time since last irinotecan dose (2.8 versus 4.8 months), respectively in the cetuximab and cetuximab/irinotecan arms. The G13D arm contained 51 patients; of the 53 individuals enrolled, 2 patients were excluded for not being truly refractory to irinotecan.
Observations from the ICECREAM trial
Results for the G13D cohort of patients reported at the ECC show 6 month PFS rates of 10% (95% CI 2%, 26%) in the cetuximab arm compared to 23% (95% CI 9%, 40%) in the cetuximab/irinotecan arm, hazard ratio (HR) 0.75 (95% CI 0.42, 1.33). The median time to progression was similar in the respective arms at 2.5 versus 2.6 months.
No patients in either treatment arm achieved complete response. While patients receiving cetuximab monotherapy showed no partial response (PR), stable disease (SD) was achieved by 58% of patients. In the cetuximab/irinotecan arm, 9% of patients achieved PR and 70% of patients showed SD.
One or more grade 3/4 event occurred in 11 (44%) patients receiving monotherapy and in 16 (64%) patients receiving combination therapy, consistent with previous studies.
Eric Van Cutsem of the Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium, who discussed the study results, said that his interpretation of the study findings is that there is no evidence to treat G13D mutant colorectal cancer with cetuximab or panitumumab monotherapy. Although there are data on synergistic activity of irinotecan plus cetuximab in irinotecan refractory cell lines and patients (who are sensitive to cetuximab), this does not apply to G13D mutant colorectal cancer. He added that the ICECREAM study is a stimulus for prospective trials in collaborative way; he is looking forward to data in KRAS wild type patients in the ICECREAM study; focus should be on markers beyond RAS for determination of resistance to anti-EGFR antibodies; and although we have learned a lot, the determination of optimal use of anti-EGFR antibodies remains a challenge.
Based on these results, the AGITG researchers concluded that combination therapy may warrant further evaluation to confirm whether irinotecan acts synergistically with EGFR inhibitors in patients with CRC and G13D mutation. However, the lack of response with single agent cetuximab in patients with G13D mutations suggest this question should not be further explored.
The ICECREAM study is the first trial to date to address an important question in patients with a rare molecular subtype of colorectal cancer, KRAS G13D mutations, providing prospective data on treatment in this cohort and confirming that timely recruitment to such studies can occur with excellent international collaborations. These results contribute to the management of patients with G13D mutated, chemorefractory colorectal cancer.
Disclosure: The study was sponsored by the Australian Gastrointestinal Treatment Group (AGITG) having received an unrestricted grant from Merck Serono.
32LBA The AGITG ICECREAM Study: The Irinotecan Cetuximab Evaluation and Cetuximab Response Evaluation Amongst Patients with a G13D Mutation- analysis of outcomes in patients with refractory metastatic colorectal cancer harbouring the KRAS G13D mutation